1. Field of the Invention
The present invention is directed to providing, preparing and using compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to selecting and preparing compounds which inhibit the enzyme cytochrome P450RAI, many of which are derivatives of phenylacetic or heteroarylacetic acid, and using said compounds for treatment of diseases and conditions which are normally treated by retinoids.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn's disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
Several compounds having retinoid-like activity are actually marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural product, biosynthesized and present in a multitude of human and mammalian tissues and is known to play an important rule in the regulation of gene expression, tissue differentiation and other important biological processes in mammals including humans. Relatively recently it has been discovered that a catabolic pathway in mammals, including humans, of natural retinoic acid includes a step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoic acid inducible).
Several inhibitors of CP450RAI have been synthesized or discovered in the prior art, among the most important ones ketoconazole, liarozole and R116010 are mentioned. The chemical structures of these prior art compounds are provided below. It has also been noted in the prior art, that administration to mammals, including humans, of certain inhibitors of CP-450RAI results in significant increase in endogeneous RA levels, and further that treatment with CP450RAI inhibitors, for example with liarozole, gives rise to effects similar to treatment by retinoids, for example amelioration of psoriasis. 
The following publications describe or relate to the above-summarized role of CP450RAI in the natural catabolism of RA, to inhibitors of CP-450RAI and to in vitro and in vivo experiments which demonstrate that inhibition of CP450RAI activity results in a increases endogeneous RA levels and potential therapeutic benefits:    Kuijpers, et al., “The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin”, British Journal of Dermatology, (1998) 139: pp 380-389.    Kang, et al., “Liarozole Inhibits Human Epidermal Retinoid Acid4-Hydroxylase Activity and Differentially Augments Human Skin Responses to Retinoic Acid and Retinol In Vivo”, The Journal of Investigative Dermatology, (August 1996) Vol. 107, No. 2: pp 183-187.    Van Wauwe, et al., “Liarozole, an Inhibitor of Retinoic Acid Metabolism, Exerts Retinoid-Mimetic Effects in Vivo”, The Journal of Pharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2: pp 773-779.    De Porre, et al., “Second Generation Retinoic Acid Metabolism Blocking Agent (Ramba) R116010: Dose Finding in Healthy Male Volunteers”, University of Leuven, Belgium, pp 30.    Wauwe, et al., “Ketoconazole Inhibits the in Vitro and in Vivo Metabolism of All-Trans-Retinoic Acid”, The Journal of Pharmacology and Experimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.    White, et al., “cDNA Cloning of Human Retinoic Acid-metabolizing Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*”, The Journal of Biological Chemistry, (1997) Vol. 272, No. 30, Issue of July 25 pp 18538-18541.    Hanzlik, et al., “Cyclopropylamines as Suicide Substrates for Cytochromes P450RAI”, Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-761.    Ortiz de Montellano, “Topics in Biology—The Inactivation of Cytochrome P450RAI”, Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 201-210.    Hanzlik, et al. “Suicidal Inactivation of Cytochrome P450RAI by Cyclopropylamines>Evidence for Cation-Radical Intermediates”, J. Am. Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052.
In accordance with the present invention several previously known and several new compounds are utilized as inhibitors of CP450RAI to provide therapeutic benefit in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids and or which in healthy mammals, including humans, are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the enzyme CP450RAI that catabolyzes natural RA, endogenous RA level is elevated to a level where desired therapeutic benefits are attained. The chemical structures of certain previously known compounds which have been discovered to be inhibitors of the enzyme CP450RAI are provided in the descriptive portion of this application for patent. The chemical structures of the novel compounds which are used in the methods of treatment in accordance with the invention are summarized by Formulas 1 through 8 in the Summary Section of this application for patent. Based on these chemical structures the following art is of interest as background to the novel structures.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658; 5,130,335; 4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP 0 130,795; DE 3316932; DE 3708060; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 1.
U.S. Pat. Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 4,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP 0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press, Inc., 1990, pages 324-356; are of interest to compounds of Formula 2.
Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press Inc., (1990), pages 324-356; is of interest to compounds of Formula 3.
U.S. Pat. Nos. 5,965,606; 5,773;594; 5,675,024; 5,663,347; 5,023,341; 5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519; 4,826,969; 4,833,240; 5,037, 825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP 0 098 591; EP 0 170 105; EP 0 176 034; EP0 253,302; EP0 303 915; EP0 514 269; EP0 617 020; EP0 619 116; EP 0 661 259; DE 3316932; DE 3602473; DE 3715955; UK application GB 2190378; Eyrolles et al., J. Med. Chem., (1994), 37, 1508-1517; Graupner et al. Biochem. and Biophysical Research Communications, (,1991), 1554-1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press Inc., (1990), pages 324-356; are of interest to compounds of Formula 5.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP 0 170 105; EP 0 286 364; EP 0 514 269; EP 0 617 020; EP 0 619 116; DE 3524199; Derwert JP6072866; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 6.
U.S. Pat. Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341; 5,739,338; 5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 5,037,825; EP 0 130 795; DE 3316932; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 7.
U.S. Pat. Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154; 4,740,519; 4,826,969; 4,826,984; 4,833,240; 5,037,825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP 0 098 591; EP 0 130 795; EP 0 176 034; EP 0 253 302; EP 0 303 915; EP 0 514 269; EP 0 617 020; EP 0 619 116; EP 0 661 259; DE 3316932; DE 3602473; DE 3708060; DE 3715955; U.K. application GB 2190378; Eyrolles et al., J. Med. Chem., (1994), 37 1508, 1517; Graupner et al., Biochem. and Biophysical Research Communications, (1991) 1554-1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al. “Chemistry and Biology of Synthetic Retinoids”, published by CRC Press Inc., (1990), pages 324-356; are of interest to compounds of Formula 8.
Prior art which is of interest as background to the previously known compounds that have been discovered in accordance with the present invention to be inhibitors of cytochrome P450RAI, is identified together with the identification of these known compounds.